Orodispersible dosage unit containing an estetrol component

ABSTRACT

The invention provides an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit comprising:
         0.1-25 wt. % of estetrol particles containing at least 80 wt. % of an estetrol component selected from estetrol, estetrol esters and combinations thereof; and   75-99.9 wt. % of one or more pharmaceutically acceptable excipients;
 
the solid dosage unit comprising at least 100 μg of the estetrol component; and wherein the solid dosage unit can be obtained by a process that comprises compressing a dry blend of estetrol particles and one or more pharmaceutically acceptable excipients into a solid dosage unit.
       

     The solid dosage unit is easy to manufacture and perfectly suited for sublingual, buccal or sublabial administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This non-provisional U.S. Patent Application is a Continuation of U.S.application Ser. No. 15/185,337, filed Jun. 17, 2016, which claimspriority to European Patent Application No. 15172747.6, filed Jun. 18,2015, the contents of which are incorporated herein by their entirety byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention provides an orodispersible solid pharmaceuticaldosage unit having a weight of 30-1,000 mg and containing at least 0.1mg of an estetrol component selected from estetrol, estetrol esters andcombinations thereof. This solid dosage unit comprises:

-   -   0.1-25 wt. % of estetrol particles containing at least 80 wt. %        of the estetrol component; and    -   75-99.9 wt. % of one or more pharmaceutically acceptable        excipients.

The invention also provides a process of preparing the aforementionedsolid dosage unit.

Furthermore, the invention relates to the use of the solid dosage unitin medical treatment, female hormone replacement therapy and femalecontraception, said use comprising sublingual, buccal or sublabialadministration of the said dosage unit..

BACKGROUND OF THE INVENTION

Estetrol is a human steroid, produced by the fetal liver duringpregnancy only. This natural hormone was discovered in urine of pregnantwomen by Diczfalusy and coworkers in 1965. Estetrol has the structure ofan estrogenic steroid with four hydroxyl groups. Estetrol is synthesizedin the fetal liver from estradiol and estriol by the two enzymes 15α-and 16α-hydroxylase. After birth the neonatal liver rapidly loses itscapacity to synthesize estetrol because these two enzymes are no longerexpressed.

Estetrol reaches the maternal circulation through the placenta and wasalready detected at nine weeks of pregnancy in maternal urine. Duringthe second trimester of pregnancy high levels were found in maternalplasma, with steadily rising concentrations of unconjugated estetrol toabout 1 ng/mL (>3 nmol/L) towards the end of pregnancy. So far thephysiological function of estetrol is unknown. The possible use ofestetrol as a marker for fetal well-being has been studied quiteextensively. However, due to the large intra- and inter-individualvariation of maternal estetrol plasma levels during pregnancy thisappeared not to be feasible.

Since 2001 estetrol has been studied extensively. In humans estetrol wasshown to have a high and dose-proportional oral bioavailability and along terminal elimination half-life of about 28 hours. Results from invitro studies showed that estetrol binds highly selective to theestrogen receptors with preference for the ERα form of the receptor,unlike the estrogens ethinyl estradiol and 17β-estradiol. Also incontrast with ethinyl estradiol and especially with 17β-estradiol,estetrol does not bind to sex hormone binding globulin (SHBG) and doesnot stimulate the production of SHBG in vitro.

The properties of estetrol have also been investigated in a series ofpredictive, well validated pharmacological in vivo rat models. In thesemodels, estetrol exhibited estrogenic effects on the vagina, the uterus(both myometrium and endometrium), body weight, bone mass, bonestrength, hot flushes and on ovulation (inhibition). All these effectsof estetrol were dose-dependent with maximum effects at comparable doselevels. Surprisingly, estetrol prevented tumour development in a DMSAmammary tumour model to an extent and at a dose level similar to theanti-estrogen tamoxifen and to ovariectomy. This anti-estrogenic effectof estetrol in the presence of 17β-estradiol has also been observed inin vitro studies using human breast cancer cells.

Buccal, sublingual or sublabial administration of estetrol is mentionedin a number of patent applications, including WO 2002/094275, WO2002/094276, WO 2002/094278 and WO 2003/018026. Estetrol containingdosage units for buccal, sublingual or sublabial administration are notdescribed in these publications.

WO 2010/033832 describes an oral dosage form comprising an estriolcompound and a pharmaceutically acceptable matrix material, wherein theoral dosage form releases at least about 90% of the estriol compound ina time of less than about 300 seconds when contacted with saliva of thebuccal and/or sublingual cavity.

US 2007/286829 describes an orally administered solid dosage formcapable of delivering ethinyl estradiol with improved bioavailability,said solid dosage form comprising (i) about 0.5 μg to about 50 μg ofethinyl estradiol and (ii) an oral dissolution enhancing carrier thatprovides for at least 15% absorption of the ethinyl estradiol throughthe oral mucosa when said solid dosage form is orally administered tothe patient with 2 ounces of water or less.

U.S. Pat. No. 6,117,446 describes a buccal dosage unit for administeringa combination of steroidal active agents, comprising a compressed tabletof a bioerodible polymeric carrier and therapeutically effective amountsof an androgenic agent selected from testosterone and pharmacologicallyacceptable esters thereof, a progestin and an estrogen. The examplesdescribe buccal dosage units that were prepared by thoroughly mixing thefollowing components: estrogen, progestogen, androgen, polyethyleneoxide, carbomer and magnesium stearate. Next, the mixture was granulatedby means of fluid bed granulation and the granulate so obtained waspressed into tablets.

Oral dosage units containing estetrol have been described in severalpatent publications.

WO 2002/094276 describes a pharmaceutical composition for use in amethod of hormone replacement therapy, which method comprisesadministering to a person in need of such a therapy an effective amountof estetrol, said composition containing virtually no progestogen oranti-progestin. WO 2002/094276 describes the preparation of estetroltablets having a weight of 185 mg, containing 1.5 mg estetrol, on thebasis of the following formulation:

mg Estetrol 1.5 Polyvinylpyrrolidone 12.5 (Kollidon 25 ® ex BASF)Lactose 135.795 Microcrystalline cellulose 26.25 (Avicel PH 101  ®)Glyceryl palmitostearate 2.775 (Precirol  ®) Anhydrous colloidal silica1.0 (Aerosil 200  ®) Crospovidone (Poly- 4.0 plasdone XL  ®) Coloringagent 0.18

WO 2002/094275 describes the use of an estetrol in a method ofincreasing libido in a woman, said method comprising administering tosaid woman an effective amount of estetrol. Oral administration ismentioned as a suitable mode of administration. This patent applicationdescribes the same estetrol tablet as WO 2002/094276.

WO 2002/094279 describes the use of estetrol in a method ofcontraception in mammalian females, which method comprises the oraladministration of said estrogenic component and a progestogeniccomponent to a female of childbearing capability in an effective amountto inhibit ovulation. The following formulation for a 185 mg estetroltablet is described in this international patent application.

mg Estetrol 1.5 Levonorgestrel 0.15 Polyvinylpyrrolidone 13.5 (Kollidon25 ® ex BASF) Lactose 135.645 Microcrystalline cellulose 26.25 (AvicelPH 101  ®) Glyceryl palmitostearate 2.775 (Precirol  ®) Anhydrouscolloidal silica 1.0 (Aerosil 200  ®) Crospovidone (Poly- 4.0 plasdoneXL  ®) Coloring agent 0.18

WO 2003/041718 describes the use of estetrol in a method of hormonereplacement in mammals, which method comprises the oral administrationof estetrol and a progestogenic component to a mammal in an effectiveamount to prevent or treat symptoms of hypoestrogenism. This patentapplication describes the same estetrol tablet as WO 2002/094279.

WO 2007/081206 describes the use of estetrol in a method of treating anacute vascular disorder in a mammal, said method comprising orallyadministering to said mammal, upon demand, an effective amount of theestetrol to the mammal. This patent application describes thepreparation of hard gelatine capsules, containing 100 mg estetrol and 25mg sildenafil citrate per capsule.

WO 2008/156365 describes the use of estetrol in the treatment ofMeconium Aspiration Syndrome (MAS) in a newborn infant, said treatmentcomprising administering an effective amount of estrogen to said newborninfant within 7 days after birth. The international patent applicationdescribes a suppository for use in newborn infants comprising at least 1μg of estrogen, said suppository further being characterized by amaximum diameter of less than 10 mm and a weight of less than 0.5 g. Theexcipient contained in the suppository may be based on lipid materialthat melts at body temperature or it may be based on a hydrophiliccomponent that dissolves or disintegrates when it comes into contactwith water.

SUMMARY OF THE INVENTION

The present invention provides an orodispersible solid pharmaceuticaldosage unit containing an estetrol component. The dosage unit rapidlyreleases the estetrol in aqueous environment. The solid dosage unit iseasy to manufacture by direct compression and perfectly suited forsublingual, buccal or sublabial administration. Sublingual, buccal andsublabial administration each offer the advantages that the estetrolcomponent does not have to pass through the digestive system and avoidsfirst-pass liver exposure. Furthermore, these modes of administrationprovide a rapid onset of action.

The solid dosage unit according to the present invention has a weightbetween 30 and 1,000 mg and contains at least 100 μg of an estetrolcomponent selected from estetrol, estetrol esters and combinationsthereof; and comprises:

-   -   0.1-25 wt. % of estetrol particles containing at least 80 wt. %        of the estetrol component; and    -   75-99.9 wt. % of one or more pharmaceutically acceptable        excipients.

This solid dosage is obtainable by a process comprising:

-   -   providing estetrol particles containing at least 80 wt. % of an        estetrol component selected from estetrol, estetrol esters and        combinations thereof, said estetrol particles having a volume        median diameter in the range of 2 μm to 50 μm;    -   preparing a dry blend by mixing the estetrol particles with one        or more pharmaceutically acceptable excipients; and    -   compressing the dry blend into a solid dosage unit.

Rapid and complete dissolution of the estetrol component into saliva isessential for efficient delivery of the component via sublingual, buccalor sublabial administration of the solid dosage unit. The inventors haveunexpectedly found that the estetrol component is rapidly released anddispersed into saliva and absorbed through the mucosal lining of theoral cavity if it is present in the solid dosage unit in the form ofvery small particles.

The invention also provides a process of preparing the aforementionedsolid dosage unit, said process comprising the steps of:

-   -   providing estetrol particles containing at least 80 wt. % of an        estetrol component selected from estetrol, estetrol esters and        combinations thereof, said estetrol particles having a volume        median diameter in the range of 2 μm to 50 μ;    -   preparing a dry blend by mixing 1 part by weight of the estetrol        particles with 2-1,000 parts by weight of one or more        pharmaceutically acceptable excipients; and    -   compressing the dry blend into a solid dosage unit.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 illustrates the manufacturing process flow chart used in Example3.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention relates to an orodispersible solidpharmaceutical dosage unit having a weight between 30 and 1,000 mg, saiddosage unit comprising:

-   -   0.1-25 wt. % of estetrol particles containing at least 80 wt. %        of an estetrol component selected from estetrol, estetrol esters        and combinations thereof; and    -   75-99.9 wt. % of one or more pharmaceutically acceptable        excipients; the solid dosage unit comprising at least 100 μg of        the estetrol component;

wherein the solid dosage unit can be obtained by a process comprising:

-   -   providing estetrol particles containing at least 80 wt. % of an        estetrol component selected from estetrol, estetrol esters and        combinations thereof, said estetrol particles having a volume        median diameter in the range of 2μm to 50 μm;    -   preparing a dry blend by mixing the estetrol particles with one        or more pharmaceutically acceptable excipients; and    -   compressing the dry blend into a solid dosage unit.

The term ‘estetrol’ as used herein refers to 1,3,5(10)-estratrien-3,15α,16α,17β-tetrol or 15α-hydroxyestriol as well ashydrates of estetrol, e.g. estetrol monohydrate.

The term orodispersible dosage unit' as used herein refers to a dosageunit that is designed to rapidly disintegrate in the oral cavity when itcomes into contact with saliva and to disperse the estetrol componentinto the saliva so it may be absorbed through the mucosal lining of theoral cavity.

The term ‘sublingual’ as used herein refers to the pharmacological routeof administration by which the estetrol component diffuses into theblood through tissues under the tongue.

The term ‘buccal’ as used herein refers to the pharmacological route ofadministration by which the estetrol component diffuses into the bloodthrough tissues of the buccal vestibule, the area inside the mouthbetween the lining of cheek (the buccal mucosa) and the teeth/gums.

The term sublabial' as used herein refers to the pharmacological routeof administration by which the estetrol component is placed between thelip and the gingiva.

Unless indicated otherwise, all percentages mentioned herein arepercentages by weight.

Examples of solid dosage units encompassed by the present inventioninclude tablets, dragees, lozenges and films. In accordance with apreferred embodiment, the dosage unit is a tablet, most preferably acompressed tablet.

The solid dosage unit typically has a weight between 40 and 500 mg, morepreferably between 50 and 300 mg, and most preferably between 70 and 150mg.

The solid dosage unit preferably comprises 0.5-25 wt. %, more preferably1-20 wt. % and most preferably 1.2-15 wt. % of the estetrol component.

The amount of the estetrol component contained in the solid dosage unitpreferably lies within the range of 0.3-100 mg, more preferably of0.5-40 mg and most preferably of 1-20 mg.

The estetrol component of the present invention preferably is selectedfrom the group consisting of estetrol, esters of estetrol wherein thehydrogen atom of at least one of the hydroxyl groups has beensubstituted by an acyl radical of a hydrocarbon carboxylic, sulfonicacid or sulfamic acid of 1-25 carbon atoms; and combinations thereof.Even more preferably, the estetrol component is estetrol (includingestetrol hydrates). Most preferably, the estetrol component contained inthe dosage unit is estetrol monohydrate.

The particle size of the estetrol particles in the solid dosage unitshould be adequate for achieving sufficient absorption of the estetrolcomponent after sublingual, buccal or sublabial administration. Theestetrol particles within the solid dosage unit and (independently) theestetrol particles used in the preparation of the solid dosage unitpreferably have a volume median diameter in the range of 3 μm to 35 μm,more preferably in the range of 4μm to 25 pm and most preferably in therange of 5 μm to 15 μm.

The estetrol particles within the solid dosage unit and (independently)the estetrol particles used in the preparation of the solid dosage unitpreferably contain not more than a limited amount of particles with aparticle size in excess of 60 μm Preferably, not more than 10 vol. % ofmore than 60 μm (D₉₀), more preferably not more than 5 vol. % of theestetrol particles have a particle size of more than 60 μm (D₉₅). Evenmore preferably, not more than 10 vol. % of more than 40 μm (D₉₀), morepreferably not more than 5 vol. % of the estetrol particles have aparticle size of more than 40 μm (D₉₅).

The particles size distribution of the estetrol particles, and of otherparticulate materials used in the present process, may suitably bedetermined by means of laser diffraction. The particle size distributionof the estetrol particles within the solid dosage unit can suitably bedetermined using spectroscopic techniques, e.g. Raman mapping.

The solid dosage unit of the present invention offers the advantage thatthe estetrol component is rapidly released when the dosage unit isintroduced into the oral cavity and comes into contact with saliva. Therate of release of the estetrol component from the dosage unit cansuitably be determined using the dissolution test described in theExamples, or a disintegration test according to Ph. Eur. 2.9.1(“Disintegration of tablets and capsules”) and USP<701>(“Disintegration”), also described in the Examples. The soliddosage unit of the present invention, when subjected to theaforementioned dissolution test, typically releases at least 50%, morepreferably at least 70% and most preferably at least 80% of the estetrolcomponent after 5 minutes. The solid dosage unit of the presentinvention, when subjected to the aforementioned disintegration test,typically disintegrates within less than 5 minutes, more preferablywithin less than 2 minutes, still more preferably within less than 1,5minutes, still more preferably within less than 1 minute, still morepreferably within less than 45 seconds, and most preferably within lessthan 30 seconds.

The estetrol particles employed in the solid dosage unit and in thepresent process preferably contain at least 90 wt. % of the estetrolcomponent, more preferably at least 95 wt. % of the estetrol componentand most preferably at least 99 wt. % of the estetrol component. Besidesthe estetrol component, the estetrol particles can suitably containpharmaceutically acceptable ingredients that aid dispersion of thedosage unit and dissolution and absorption of the estetrol component.Examples of such ingredients include microcrystalline cellulose,tensioactive agents, cosolvents, absorption enhancer, superdisintegrantsand buffering agents.

The estetrol particles typically represent between 0.5-35 wt. % of thedosage unit. More preferably, the estetrol particles represent 1-22 wt.%, most preferably 1.2-15 wt. % of the dosage unit.

The dosage unit of the present invention preferably contains 50-99.5 wt.%, more preferably 55-90 wt. % and most preferably 60-88 wt. % of fillerselected from maltose, fructose, sucrose, lactose, glucose, galactose,trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt,microcrystalline cellulose, calcium salts (e.g. calcium phosphates) andcombinations thereof.

According to a particularly preferred embodiment, the dosage unitcontains 30-99.5 wt. %, more preferably 50-90 wt. % and most preferably60-80 wt. % of filler selected from lactose, xylitol, sorbitol,erythritol, mannitol, microcrystalline cellulose and combinationsthereof.

Advantageously, the dosage unit contains at least 20 wt. % of sugaralcohol selected from mannitol, xylitol and combinations thereof. Morepreferably, the dosage unit contains 30-90 wt. % of sugar alcoholselected from mannitol, xylitol and combinations therof Most preferably,the dosage unit contains 40-80 wt. % of sugar alcohol selected frommannitol, xylitol and combinations thereof.

Dosage unit according to any one of the preceding claims, wherein thedosage unit contains 0.1-20 wt. %, more preferably 0.2-10 wt. % and mostpreferably 1-5 wt. % of a disintegrating agent selected from modifiedstarches (e.g. sodium salt of carboxymethyl starch), crosslinkedpolyvinyl pyrrolidone, crosslinked carmellose and combinations thereof.

The combination of estetrol particles, filler and disintegrating agenttypically constitutes at least 70 wt. % of the solid dosage unit. Morepreferably, said combination constitutes at least 80 wt. % and mostpreferably at least 90 wt. % of the dosage unit.

The solid dosage unit of the present invention preferably contains 0-60wt. %, more preferably 5-40 wt. % and most preferably 10-35 wt. %microcrystalline cellulose.

According to another preferred embodiment, the dosage unit contains0.1-2 wt. %, more preferably 0.2-1.5 wt. % and most preferably 0.5-1 wt.% of lubricant selected from sodium stearyl fumarate, magnesiumstearate, stearic acid, sodium lauryl sulfate, talc, polyethyleneglycol, calcium stearate and mixtures thereof.

Other excipients that may suitably be incorporated in the dosage includemucoadhesive agents, flavouring, colouring, sweeteners (other than sweettasting fillers), glidents and combinations thereof.

The solid dosage unit may contain one or more other pharmaceuticallyactive ingredients besides the estetrol component. Examples of suchother pharmaceutically active ingredients include steroid hormones. Thesolid dosage unit of the present invention preferably contains 0.05-10mg, more preferably 0.1-5 mg of one or more progestogens, preferably oneor more progestogens selected from progesterone, levonorgestrel,norgestimate, norethisterone, norethi steron-acetate (NETA),dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel (=etonogestrel), 17-deacetyl norgestimate,19-norprogesterone, acetoxypregnenolone, allylestrenol, anagestone,chlormadinone, cyproterone, demegestone, desogestrel, dienogest,dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate,flurogestone acetate, gastrinon, gestodene, gestrinone,hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol(=lynoestrenol), medrogestone, medroxyprogesterone, megestrol,melengestrol, nestorone, nomegestrol, nomegestrol-acetate (NOMAC),norethindrone (=norethisterone), norethynodrel, norgestrel (includesd-norgestrel and dl-norgestrel), norgestrienone, normethisterone,progesterone, quingestanol,(17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3-one,tibolone, trimegestone, algestone acetophenide, nestorone, promegestone,17-hydroxyprogesterone esters, 19-nor-17hydroxyprogesterone,17alpha-ethinyl-testosterone, 17alpha-ethinyl-19-nor-testosterone,d-17beta-acetoxy-13beta-ethyl-17alpha-ethinyl-gon-4-en-3 -one oxime andprodrugs of these compounds. Preferably the one or more progestogensused in accordance with the present invention is selected from the groupconsisting of progesterone, desogestrel, etonogestrel, gestodene,dienogest, levonorgestrel, norgestimate, norethisterone,norethisteron-acetate (NETA), nomegestrol, nomegestrol-acetate (NOMAC),drospirenone, trimegestone, nestorone and dydrogesterone.

The solid dosage unit according to the present invention preferablycontains 0.05-100 mg, more preferably 0.1-50 mg of one or moreandrogens, preferably one or more androgens selected from testosterone,dehydroepiandrosterone (DHEA); DHEA-sulphate (DI-TEAS); testosteroneesters (e.g. testosterone undecanoate, testosterone propionate,testosterone phenylpropionate, testosterone isohexanoate, testosteroneenantate, testosterone bucanate, testosterone decanoate, testosteronebuciclate); methyltestosterone; mesterolon; stanozolol; androstenedione;dihydrotestosterone; androstanediol; metenolon; fluoxymesterone;oxymesterone; methandrostenolol; MENT and prodrugs of these compounds.Most preferably the one or more androgens are selected from the groupconsisting of testosterone, DHEA and MENT.

Another aspect of the present invention relates to the use of theaforementioned solid dosage unit in medical treatment, in female hormonereplacement therapy or in female contraception, said use comprisingsublingual, buccal or sublabial administration of the dosage unit.Examples of medical treatment in which the solid dosage unit of thepresent invention may suitably be used include treatment of osteoporosisand estrogen add-back treatment in endometriosis, breast cancer orprostate cancer. In accordance with a preferred embodiment, the soliddosage unit is used in female hormone replacement therapy or femalecontraception. Most preferably, the solid dosage is used in femalehormone replacement therapy, especially to treat vulvovaginal atrophyand/or vasomotor symptoms.

The use of the solid dosage unit in medical treatment, in female hormonereplacement therapy or in female contraception, typically comprisessublingual, buccal or sublabial administration of the dosage unit toprovide at least 0.1 mg, more preferably 0.5-100 mg and most preferably1-40 mg of the estetrol component.

To treat vulvovaginal atrophy the dosage unit is preferably administeredin an amount sufficient to provide at least 0.1 mg of the estetrolcomponent. More preferably, the administered dosage unit provides atleast 0.5 mg, most preferably at least 1 mg of the estetrol component.In the treatment of vulvovaginal atrophy the dosage unit is preferablyadministered in an amount that provides no more than 50 mg, morepreferably not more than 20 mg and most preferably not more than 10 mgof the estetrol component.

To treat vasomotor symptoms the dosage unit is preferably administeredin an amount sufficient to provide at least 0.2 mg of the estetrolcomponent. More preferably, the administered dosage unit provides atleast 1 mg, most preferably of at least 2 mg of the estetrol component.In the treatment of vasomotor symptoms the dosage unit is preferablyadministered in an amount that provides no more than 100 mg, morepreferably not more than 40 mg and most preferably not more than 20 mgof the estetrol component.

Typically, these uses of the solid dosage unit comprise once dailyadministration of the dosage unit during a period of at least 1 week,more preferably of at least 2 weeks. During these periods the soliddosage unit is preferably administered to provide a daily dose of atleast 0.05 mg, more preferably of 0.1-40 mg and most preferably of0.2-20 mg of the estetrol component.

To treat vulvovaginal atrophy the dosage unit is preferably administeredto provide a daily dose of at least 0.1 mg of the estetrol component.More preferably, the dosage unit is administered to provide a daily doseof 0.5-20 mg, most preferably of 1-10 mg of the estetrol component.

To treat vasomotor symptoms the dosage unit is preferably administeredto provide a daily dose of at least 0.2 mg of the estetrol component.More preferably, the dosage unit is administered to provide a daily doseof 1-40 mg, most preferably 2-20 mg of the estetrol component.

Yet another aspect of the invention relates to a process of preparing asolid dosage unit as described herein before, said process comprisingthe steps of:

-   -   providing estetrol particles containing at least 80 wt. % of an        estetrol component selected from estetrol, estetrol esters and        combinations thereof, said estetrol particles having a volume        median diameter in the range of 2 μm to 50 μm;    -   preparing a dry blend by mixing 1 part by weight of the estetrol        particles with 2-1,000 parts by weight of one or more        pharmaceutically acceptable excipients; and    -   compressing the dry blend into a solid dosage unit.

The process of the present process preferably does not comprise additionof liquid solvent during or after the combining of the estetrolparticles and the one or more pharmaceutically acceptable exci pi ents.

In the present process the dry blend that is compressed into a soliddosage unit is preferably produced by combining the estetrol particleswith the one or more pharmaceutically acceptable excipients in a weightratio that is in the range of 1:3 to 1:500, more preferably in the rangeof 1:4 to 1:100 and most preferably in the range of 1:5 to 1:10.

The dry blend that is compressed into the solid dosage unit preferablycontains 50-99.5 wt. %, more preferably 55-90 wt. % and most preferably60-88 wt. % of filler as defined herein before.

According to a particularly preferred embodiment the dry blend contains30-99.5 wt. %, more preferably 50-90 wt. % and most preferably 60-80 wt.% of filler selected from lactose, xylitol, sorbitol, erythritol,mannitol, microcrystalline cellulose and combinations thereof.

Sugar alcohol selected from mannitol, xylitol and combinations thereofis advantageously contained in the dry blend in a concentration of atleast 20 wt. %. More preferably, said sugar alcohol is contained in thedry blend in a concentration of 30-90 wt. %, most preferably of 40-80wt. %.

According to another preferred embodiment, the dry blend contains 0.1-20wt. %, more preferably 0.2-10 wt. % and most preferably 1-5 wt. % of adisintegrating agent selected from modified starches, croslinkedpolyvinylpyrrolidone, crosslinked carmellose and combinations thereof.

The combination of estetrol particles, filler and disintegrating agenttypically constitutes at least 70 wt. % of the dry blend. Morepreferably, said combination constitutes at least 80 wt% and mostpreferably at least 90 wt. % of the dry blend.

The solid dosage unit of the present invention preferably contains 0-60wt. %, more preferably 5-40 wt. % and most preferably 10-35 wt. %microcrystalline cellulose.

The dry blend employed in the present process preferably contains 0-60wt. %, more preferably 5-40 wt. % and most preferably 10-35 wt. %microcrystalline cellulose.

The dry blend that is compressed into the solid dosage unit preferablycontains 0.1-2 wt. %, more preferably 0.2-1.5 wt. % and most preferably0.5-1 wt. % of lubricant selected from sodium stearyl fumarate,magnesium stearate, stearic acid, sodium lauryl sulfate, talc,polyethylene glycol, calcium stearate and mixtures thereof.

The dry blend is preferably compressed into a solid dosage unit by meansof direct compression.

The solid dosage units obtained by the present method can be packaged indifferent ways.

Preferably, the dosage units are packaged in a blister pack containingat least 14 dosage units.

The invention is further illustrated by means of the followingnon-limiting examples.

EXAMPLES

Dissolution Test

The dissolution test described below can be used to study thedissolution behaviour of orodispersible dosage units.

Dissolution Apparatus

-   -   Paddle and basket dissolution tester VanKel VK 7010 or VK 7025,        autosampler VK 8000, 1000 mL dissolution vessels and porous        micron filters (35 pin)

Dissolution Medium

-   -   Transfer 9,000 ml of demineralised water into a volumetric flask        of 10,000 ml.    -   Add 68.05 g of KH₂PO₄ and 8.96 g NaOH and stir the solution        until everything is dissolved.    -   Mix the solution and adjust the pH to 6.8 with NaOH or        phosphoric acid, if necessary and make up to volume with        demineralised water.

Dissolution Procedure

-   -   Transfer 900 ml of Dissolution Medium into each vessel of the        paddle apparatus.    -   Assemble the apparatus, warm the medium to 37±0.5° C., and        remove the thermometer.    -   Place in each of the six vessels one tablet at the bottom before        starting the rotation of the paddles.    -   Start the rotation of the paddles immediately.    -   Use a stirring speed of 50 rpm.    -   Take samples of 5 ml from the dissolution vessels after 5, 10,        20, 30, 45, 60, 75 and 90 minutes for a complete dissolution        profile. Take the sample from a position midway between the        surface of the dissolution medium and the top of the paddle        blade and not less than 10 mm from the vessel wall. The removed        dissolution volume is not replaced by fresh dissolution medium.

Estetrol concentrations in the samples were determined by means of HPLCusing estetrol stock solutions as a reference.

Preparation of Mobile Phase (MP) Phosphate Buffer

-   -   Transfer 1.15 g of NH₄H₂PO₄ (10 mM) into a 1,000 ml of        demineralised water, dissolve it and adjust the pH to 3.0 with        phosphoric acid.

HPLC Apparatus

-   -   Alliance 2695 Separations module consisting of a quaternary        solvent delivery system, a variable volume injector, a        temperature controlled autosampler, column thermostat and

Photodiode array detector 2996 (all by Waters)

-   -   Analytical colunm: Symmetry C18, 3.9×150 mm, dp=5 μm (ex Waters)    -   Guard column: Security guard columg C18, 4×3 mm (Phenomenex)    -   Flow: 1.0 mL/min    -   Detection: UV @ 280 nm    -   Column temperature: 30° C.    -   Autosampler temperature: 10° C.    -   Injection volume: 100 μL    -   Run time: 12 min

Elution Gradient

Time Acetonitrile Phosphate (min) (%) buffer (%)  0 20 80  9 75 25 10 2080 12 20 80

The dissolution tests are conducted in triplicate.

Particle Size Measurements

Particle size distribution of estetrol monohydrate is performed using aMALVERN MASTERSIZER MICROPLUS laser particle size analyzer.

Preparation of Dispersion Medium:

-   -   Weigh 1 g of estetrol monohydrate and lg of sorbitan trioleate        into a flask.    -   Add 1 litre of n-hexane and mix for at least 1 hour at room        temperature    -   Filter through a 0.45 μm filter.

Sample Preparation:

-   -   Put 100 mg of sample in a 25 mL beaker.    -   Add some drops of dispersion medium.    -   Mix carefully with a glass rod to suspend well the powder.    -   Add 10 mL of dispersion medium.    -   Perform the analysis with the sample dispersion unit's speed at        3000-3500 rpm.

Analysis:

Particle size measurements are performed three times using the samedispersion. result is obtained by averaging the results of the threedeterminations.

Example 1

A sublingual tablet is prepared by means of the procedure describedbelow.

A tabletting mixture having the composition shown in Table 1 is preparedby dry blending, using a low shear mixer.

TABLE 1 Ingredients Wt. % Milled estetrol ¹ 12.5 Mannitol 47.5 Lactose30 PVP (polyvinylpyrrolidone) 4 Sodium crosscarmellose 4 Flavour 0.5Aspartame 1 Magnesium stearate 0.5 ¹ D _((v;0.5)) = 15 μm

The tabletting mixture is compressed into 80 mg round tablets with adiameter of 6.5 mm. The estetrol content of these tablets is 10 mg.

Example 2

A sublingual tablet is prepared by means of the procedure describedbelow.

A tabletting mixture having the composition shown in Table 2 is preparedby dry blending using a low shear mixer.

TABLE 2 Ingredients Wt. % Milled estetrol ¹ 12.5 Mannitol 37.5 Xylitol10 Microcrystalline cellulose 33 Sodium starch glycolate 5 Flavour 0.5Aspartame 1 Magnesium stearate 0.5 ¹ D _((v;0.5)) = 15 μm

The tabletting mixture is compressed into 80 mg round tablets with adiameter of 6.5 mm. The estetrol content of these tablets is 10 mg.

Example 3

Five different sets of sublingual tablets (formulations A to E) wereprepared by means of the procedure described below and illustrated inFIG. 1.

The target amounts of estetrol per tablet were as follows: 100 μg forformulation A, 1 mg for formulation B, and 10 mg for formulations C, Dand E.

The target weights for the tablets were as follows: 30 mg forformulation A, 1000 mg for formulation B, and 80 mg for formulations C,D and E.

The estetrol was mixed with a part of the main diluent and screened overa 800 μm screen. All other excipients were also screened over a 800 μmscreen.

The materials were weighed and transferred into the mixing container(except for magnesium stearate) and mixed for 15 minutes. Finally,magnesium stearate was added and mixed for a further 3 minutes.

Compression was executed using a single punch machine equipped with aproper punch (5 mm punch for 30 mg tablets (A), 6 mm for 80 mg tablets(C, D and E) and 15 mm for 1000 mg tablets (B)).

Disintegration time was quantified according to the known protocoldescribed in Ph. Eur. 2.9.1 (“Disintegration of tablets and capsules”),and in USP <701> (“Disintegration”) using water as the specified liquid.

Hardness was measured using the known protocol described in Ph. Eur.2.9.8 (“Resistance to crushing of tablets”).

The final formulations and corresponding tablet results can be found inTables 3 and 4 below.

All formulations were prepared and processed into tablets withoutencountering any specific difficulties. It should be noted that a goodflowing diluent was used in all formulations to overcome flowabilityissues and that the concentration of magnesium stearate was at least1.5% to avoid sticking.

TABLE 3 details of the formulations in Wt. % Formulation # A B C D EMilled Estetrol ¹ 0.33 0.1 12.50 12.40 12.35 Mannitol 83.14 83.47 71.0048.47 38.62 Maize starch 10.01 10.00 10.00 Crospovidone 5.01 5.01 4.99Lactose 29.68 PVP (polyvinylpyrrolidone) 3.98 Sodium crosscarmellose3.98 Xylitol DC 9.91 Microcrystalline cellulose 32.66 Sodium starchglycolate 4.97 Magnesium stearate 1.51 1.51 1.50 1.49 1.48 ¹ D_((v;0.5)) = 15 μm

TABLE 4 experimentally determined characteristics of the Tablets Test(average result Disintegration of 6 samples) time Hardness WeightFormulation # (min:sec) (N) (mg) A 0:53 39.57 33.22 B 1:07 86.07 1060.37C 0:39 57.49 81.16 D 0:39 42.71 78.48 E 0:38 37.29 76.49

It can be seen that all tablets were obtained with a final weight closeto their target weight and that the disintegration times, even for thelargest lg tablet, were very short, in accordance with the intendedsublingual, buccal or sublabial administration route for these tablets.Finally, the hardness of all tablets was within a very acceptable range.

Example 4

A randomized, open-label, two-period, cross-over, pharmacokinetic studyis conducted to compare sublingual bioavailability of 10 mg estetroladministered in one 100 mg tablet with oral availability of estetrolcontained in a 83 mg tablet containing 10 mg estetrol. These tablets areadministered sublingually and orally to healthy female volunteers underfasting conditions.

Ten healthy female subjects are selected on the basis of the followingcriteria: age of 45-65 years (inclusive), nonsmokers or past smokers (atleast 6 months before dosing), body-mass index (BMI)=18.5 to 30 kg/m²(inclusive at the time of the screening).

The composition of the 100 mg sublingual tablets is described in Table 5below.

TABLE 5 Quantity (Wt. %) Function Milled Estetrol ¹ 10 Active ingredientLudiflash ® ² 84 Diluent/binder/super disintegrant Kollidon CL-SF ® ³ 3Super disintegrant Magnesium stearate 3 Lubricant ¹ D _((v;0.5)) = 15 μm² A mixture of mannitol (90 wt. %), Kollidon CL-SF ® ³ (5 wt. %) andKollicoat ® SR30D (a polyvinyl acetate dispersion in povidone) (5 wt. %)³ crospovidone superfine grade

These tablets have a very fast disintegration time (of 40 seconds onaverage).

At the start of the first and the second period of the study, between07:00 am and 07:28 am, 5 subjects receive a single dose of thesublingual formulation of estetrol by administering one estetrol tablet(tablet weight 100 mg; 10 mg estetrol) and 5 subjects receive a singleoral dose of the oral estetrol formulation by administering one estetroltablet (tablet weight 83 mg; 10 mg estetrol), ingested together with 200ml water.

Subjects are required to fast for at least 10 hours prior to tabletadministration and for at least 4 hours after administration. Drinkingof water or beverages is not permitted within 1 hour before the drugadministration. Subjects receive 200 ml of water 1 hour prior to and 2hours after tablet administration. Subjects are free to drink water andfruit tea from 4 hours following the tablet administration. Standardizedmeals are provided 10.5 hours before and 4, 6, 9, and 13 hours aftertablet administration.

The sequence of events that occurs during the first and second period isshown in Table 6:

TABLE 6 Event First period Day 1 Confinement from 19:00 Day 2 Dosing,blood and urine sampling, confinement Day 3 Exit procedure, confinementtill 8 am Days 4-8 Return visits Days 9-13 Wash out Second period Day 14Confinement from 19:00 Day 15 Dosing, blood and urine sampling,confinement Day 16 Exit procedure, confinement till 8 am Days 17-21Return visits Days 22-26 Wash out Day 27 Administration of a progestinDay 28 Phone call, progestin withdrawal test check

The blood and urine sampling schedule used in this study is shown inTable 7.

TABLE 7 Blood Blood collection (4 ml) is performed prior to admini-sampling stration of the tablet (0), and subsequently 0:10, 0:15, 0:20,0:25, 0:30, 0:35, 0:40, 0:45, 0:50, 0:55, 1:00, 1:10, 1:20, 1:30, 2, 3,4, 6, 10, 16, 24, 48, 72, 96, 120, 144 hours after administration. Totalnumber of blood collections in each period is 27. Urine Urine collectionis performed prior to administration sampling of the tablet and 2, 4, 8,12, 24, 48, 72, 96, 120 and 144 hours after administration. Total numberof urine collections in each period is 11.

The estetrol concentration in the collected blood samples is determinedby means of HPLC/MS/MS. The concentrations of glucuronided estetrol(D-ring) in the urine samples is also determined with the help ofHPLC/MS/MS.

Results of these analyses show that the bioavailability of sublinguallyadministered estetrol is comparable or even superior to orallyadministered estetrol. Furthermore, the data suggest that sublinguallyadministered estetrol has an earlier bioavailability compared to orallyadministered estetrol. Sublingual estetrol has less impact on a liverfunction parameter.

1. An orodispersible solid pharmaceutical dosage unit having a weightbetween 30 and 1,000 mg, the dosage unit comprising: (a) 0.1-25 wt. % ofestetrol particles containing at least 80 wt. % of an estetrol componentselected from estetrol, estetrol esters and combinations thereof; and(b) 75-99.9 wt. % of one or more pharmaceutically acceptable excipients;wherein the solid dosage unit contains at least 100 μg of the estetrolcomponent; and wherein the solid dosage unit can be obtained by aprocess comprising: (i) providing estetrol particles having a volumemedian diameter between 2 μm to 50 μm and comprising at least 80 wt. %of an estetrol component selected from estetrol, estetrol esters andcombinations thereof; (ii) mixing the estetrol particles with one ormore pharmaceutically acceptable excipients to obtain a dry blend; and(iii) compressing the dry blend into a solid dosage unit.
 2. The dosageunit according to claim 1, wherein the dosage unit has a weight between40 and 500 mg.
 3. The dosage unit according to claim 1, wherein thedosage unit contains 0.5-25 wt. % of the estetrol component.
 4. Thedosage unit according to claim 1, wherein the dosage unitcontains.0.3-100 mg of the estetrol component.
 5. The dosage unitaccording to claim 1, wherein the estetrol component is estetrol.
 6. Thedosage unit according to claim 1, wherein the estetrol particles have avolume median diameter of 3-35 μm.
 7. The dosage unit according to claim1, wherein the dosage unit contains 50-99.5 wt. % of filler selectedfrom maltose, fructose, sucrose, lactose, glucose, galactose, trehalose,xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt,microcrystalline cellulose, calcium salts and combinations thereof. 8.The dosage unit according to claim 7, wherein the filler is selectedfrom lactose, xylitol, sorbitol, erythritol, mannitol, microcrystallinecellulose and combinations thereof.
 9. The dosage unit according toclaim 7, wherein the dosage unit contains at least 20 wt. % of sugaralcohol selected from mannitol, xylitol and combinations thereof. 10.The dosage unit according to claim 1, wherein the dosage unit contains0.1-20 wt. % of a disintegrating agent selected from modified starches,crosslinked polyvinyl pyrrolidone, crosslinked carmellose andcombinations thereof.
 11. The dosage unit according to claim 1, whereinthe dosage unit contains 0-60 wt. % of microcrystalline cellulose. 12.The dosage unit according to claim 1, wherein the dosage unit contains0.1-2 wt. % of lubricant selected from sodium stearyl fumarate,magnesium stearate, stearic acid, sodium lauryl sulfate, talc,polyethylene glycol, calcium stearate and mixtures thereof.
 13. A methodfor female hormone replacement therapy, comprising sublingually,buccally or sublabially administering to a subject in need thereof thedosage unit according to claim
 1. 14. The method according to claim 13,wherein the administration is once daily for a period of at least 1week.
 15. A method of female contraception, comprising sublingually,buccally or sublabially administering to a subject in need thereof adosage unit according to claim
 1. 16. The method according to claim 15,wherein the administration is once daily for a period of at least 1week.
 17. A process of preparing an orodispersible solid pharmaceuticaldosage unit having a weight between 30 and 1,000 mg, the dosage unitcomprising: (a) 0.1-25 wt. % of estetrol particles containing at least80 wt. % of an estetrol component selected from estetrol, estetrolesters and combinations thereof; and (b) 75-99.9 wt. % of one or morepharmaceutically acceptable excipients; wherein the solid dosage unitcontains at least 100 μg of the estetrol component, the processcomprising: (i) providing estetrol particles having a volume mediandiameter between 2 μm to 50 μm and containing at least 80 wt. % of anestetrol component selected from estetrol, estetrol esters andcombinations thereof, said estetrol particles; (ii) mixing 1 part byweight of the estetrol particles with 2-1,000 parts by weight of one ormore pharmaceutically acceptable excipients to obtain a dry blend; and(iii) compressing the dry blend into a solid dosage unit.
 18. Theprocess according to claim 17, wherein the process does not compriseaddition of liquid solvent during or after the combining of the estetrolparticles and the one or more pharmaceutically acceptable excipients.19. The process according to claim 17, wherein the solid dosage unit isformed by direct compression.